Long-acting, chemical-resistant skin emollients, moisturizers, and strengtheners

ABSTRACT

The present invention relates to compounds that are two-part molecules, and compositions containing such compounds, in which one part is designed to become covalently bonded to the skin (bonding agent) and the other part (a characteristic use agent) is designed to impart some characteristic use, such as emolliency, moisturizing effect, anti-acne, anti-wrinkle, anti-pain, antimicrobial, antifungal, antiviral, anti-irritation, skin tanning and skin lightening effects, extended protection of the skin (e.g., from ultraviolet light, by incorporation of a sunscreen component; from toxic and/or irritating substances; from insects and skin parasites, by incorporation of insecticides and/or insect repellants; from free radicals or other agents, as in aging, by incorporation of antioxidants), or dyeing of hair, skin nails, wool or fur. The covalently bonded part may also be useful to impart skin strengthening effect (e.g., from shear forces) or as wound healing agents.

FIELD OF THE INVENTION

This invention relates to compounds that are two-part molecules in whichone part is designed to become covalently bonded to skin (bonding agent)and the other part (a characteristic use agent) is designed to impartsome characteristic use, such as emolliency, moisturizing effect,anti-acne, anti-wrinkle, anti-pain, antibacterial, antifungal,antiviral, anti-irritation, skin tanning and skin lightening effects,extended protection of the skin (e.g., from ultraviolet light, byincorporation of a sunscreen component; from toxic and/or irritatingsubstances; from insects and skin parasites, by incorporation ofinsecticides and/or insect repellants; from free radicals or otheragents, as in aging, by incorporation of antioxidants), or dyeing ofhair, skin, nails, wool or fur. The covalently bonded part may also beuseful to impart skin strengthening effect (e.g., from shearing forces)or as wound healing agents. The invention also relates to a method ofattaching the characteristic use agent to a water insoluble substratesuch as fibers that contain or have been modified to contain a chemicalgroup that can covalently react with the bonding agent.

BACKGROUND OF THE INVENTION

The entire surface of the human body is covered by a layer of skin,which is considered to be the largest organ in the body. It serves as abarrier between the internal organism and the external environment, toprevent toxic materials from entering into the body and to retardexcessive body water loss. In addition, it also plays a major role intemperature regulation, vitamin synthesis, excretion, sensoryperception, and processing of antigenic substances.

The skin consists of three major layers of tissue. From inside out, thelayers are the subcutaneous tissue, the dermis, and the epidermis.

The epidermis is the most superficial layer of the skin. It is dividedinto a living inner layer of viable cells (stratum Malpighii) and anoutermost laminated sheet of dry anucleate flattened horny cells(stratum corneum or horny layer).

The lowermost cell layer of the epidermis (stratum basale or stratumgerminativum) consists of the basal cells. Basal cells are continuallymoving up to the surface of the skin and undergo modification in aprocess called keratinization, and are eventually shed. The normal cellturnover time from the stratum basale to the skin surface and sheddingis approximately twenty-eight days. The stratum spinosum liesimmediately over the basal layer. This stratum consists of severallayers of cells, and the shape of these spinous cells becomesprogressively more flattened in a plane parallel to the surface of theskin as they move outward. Above the spinous cells is the stratumgranulosum, which consists of one to three layers of cells. The granularlayer is most highly developed in the regions where abundant keratin isproduced. Keratins are fibrous and insoluble proteins which are largelyresponsible for the toughness of the protective outer covering of theskin. The next stratum is the stratum lucidum, which consists of cellsthat are on the way to becoming the flat, anucleate and dead cells thatconstitute the stratum corneum. The stratum corneum is formed andcontinuously replenished by the slow upward migration of cells from thegerminative basal layer of the epidermis. The entire stratum corneum isreplaced about every two weeks in mature adults.

The condition of dry and chapped skin, which afflicts everyone at sometime, is visually characterized as a slight roughening and lessflexibility in the feel of the skin surface. Among dermatologists, thiscondition is called xerosis, in which the skin loses its suppleness,forming cracks and fissures. Environmental factors play an importantrole in bringing about this condition. Decreased humidity contributes towater loss from the skin surface, dry and cold winds increaseevaporation by convection, and low temperatures decrease stratum corneumextensibility. The increased use of synthetic detergents also helps todehydrate the stratum corneum.

The physical appearance of the skin is solely governed by the state ofthe stratum corneum. It has been demonstrated that the prime factorresponsible for dry skin is the lowered moisture content of the stratumcorneum. The factors that influence the state of hydration of thestratum corneum can be classified into three general categories: therate at which water reaches the stratum corneum from layers beneath it;the rate at which water leaves the skin surface by evaporation; and theability of the stratum corneum to hold moisture.

The stratum corneum receives water from the sweat glands and from theunderlying tissues by diffusion. At the same time, it loses water to theenvironment by evaporation. Under normal conditions, the rate at whichwater diffuses from the underlying tissues to the skin surface is slowand uniform. Experiments indicate that the major barrier against waterloss over most areas of the body is a very thin barrier at the base ofthe stratum corneum, which separates the stratum corneum from the easilyavailable water of the underlying tissues and makes it dependent uponthe surrounding environment for the moisture. As a result, at lowrelative humidity, when water tends to be lost from the surface at amore rapid rate, the stratum corneum will tend to dry out.

The softness and flexibility of the skin is determined by the moisturecontent of the stratum corneum. Contrary to older beliefs, the amount ofoil in the stratum corneum is not the essential factor in controllingthe physical appearance of the skin. Thus pieces of hardened stratumcorneum immersed in various oils do not regain their flexibility,whereas immersion in water increases their flexibility. However, theremoval of the surface lipids of the skin after organic solventtreatment also brings about the feeling of dryness. This phenomenondemonstrates the water-holding ability of the skin lipids.

Various kinds of lipids are located in the intercellular region of thestratum corneum, which are called the intercellular lipids or thestratum corneum lipids. Stratum corneum lipids are composed mainly ofceramides, free fatty acids, and cholesterol, with small proportions oftriglycerides, sterol esters, and cholesterol sulfate. The sphingolipidcontent is reported to reveal a direct relationship with permeability towater, while the neutral lipids are also suggested to make a definitecontribution to the water-retention properties of the stratum corneum.Lipid compositions of different cell populations in pig epidermis aredisclosed by Goldsmith, ed., Biochemistry and Physiology of the Skin,Oxford University Press, New York and Oxford, 1983, 364.

Dermal components of humans and animals have received much attention inthe hope of identifying markers of biologic aging. The dermis iscomposed mainly of highly stable fibers, predominantly collagen andabout 5% elastin fibers. Collagen has high tensile strength and preventsthe skin from being torn by overstretching. Elastin is an elasticprotein that maintains normal skin tension. It is the collagen-elastinfiber network that gives the skin its strength and elasticity. Hall(1976) The Aging of Connective Tissue, Academic Press, New York used“the rods and elastic band” model to demonstrate the network of thecollagen bundles in human skin. The collagen bundles are looselyarranged in a rhomboid network with individual bundles lying at anglesto one another. Intertwined amongst the collagen bundles lie singleelastin fibers. The network of collagen bundles can be distorted by theapplication of a force in one direction, but it returns to its originalform when the force is removed, in exactly the same fashion that anetwork of rigid rods will resume its shape if each crossing point isrestricted by an elastic band.

Both the collagen bundles and the elastin fibers seem to undergocharacteristic changes with time. Imayama and Braverman (1989) Am. J.Pathol. 134:1019 reported that there is a dynamic rearrangement of thecollagen and elastic fibers during the growth period of rats. Thecollagen bundles uncoil, thicken and develop a lattice pattern ofrelatively straight bundles with age. As the collagen bundlesstraighten, however, they bend and dislocate the elastin fibers. Duringadulthood, elastin fibers become increasingly tortuous and impart afrayed or porous appearance to the skin surface. The elastin fibersbecome more stretched and therefore a decrease in their originalelasticity results. These phenomena lead to the looseness, sagging andwrinkling of aged skin.

Skin care products can be used to prevent excessive water loss or torestore the high moisture content of the stratum corneum. There are twogroups of cosmetic products available for the treatment of dry skinconditions, emollients and moisturizers.

Emollients, often termed skin conditioners, increase and maintainhydration by lubricating or occluding the skin surface. They reduce theevaporative loss of water from the outside of the skin and cause abuildup of water in the stratum corneum. Emollients include a very widerange of compounds. They are all water-insoluble materials. Petrolatumis the most efficient emollient for protecting dry skin. Lanolin (afatty secretion from sheep's wool, which consists of a mixture of fattyacid esters of the sterols, lanosterol and agnosterol), fatty acids,fatty alcohols, triglyceride esters, wax esters, and esters ofpolyhydric alcohols are all common emollients. Idson (1992) Cosm. &Toil. 107: 69.

Moisturizers are composed of hygroscopic substances. They often containhumectants, substances that attract moisture to the skin, such as urea,glycerin, propylene glycol, sorbitol, pyrrolidone carboxylic acid (PCA),or sodium lactate, to impart or restore moisture to the stratum corneum.Loden et al. (1994) “Product Testing—Testing of Moisturizers” inBioengineering of the Skin: Water and the Stratum Corneum, Elsner etal., eds., CRC Press, Boca Raton, Fla., 275.

In order to evaluate moisturizer efficacy, and the irritation andbarrier destruction potentials of soaps and solvents, the term“transepidermal water loss” (TEWL) was introduced. It is used toindicate the amount of water vapor passing through the stratum corneumby passive diffusion. In other words, TEWL is a true reflection ofstratum corneum barrier function for water only in the absence of sweatgland activity. Rothman, “Insensible Water Loss” in Physiology andBiochemistry of the Skin, University of Chicago, 1954, 233.

The mathematical principle governing the diffusion of water throughstratum corneum is Fick's law. TEWL is calculated according to thefollowing integrated form:J _(s) =K _(m) D(c _(s)/δ)  eqn. 1where

-   -   J_(s)=steady state flux of water (g cm⁻²s⁻¹);    -   K_(m)=partition coefficient;    -   D=diffusion coefficient of water (cm²s⁻¹);    -   δ thickness of the membrane (cm);    -   c_(s)=concentration gradient of water across the stratum corneum        (g cm⁻³).

The water content of the innermost layer of the stratum corneum is inequilibrium with the adjacent moist granular layer, which is in turn inequilibrium with the drier environment surrounding the skin. Thus, thereexists a concentration gradient of water within the stratum corneum thatresults in a continuous diffusion of water from within the body throughthe skin and into the environment. The wetter the surface layer, thesmaller the concentration gradient and the smaller should be the TEWL.

Upon hydration, the stratum corneum thickness δ increases due toswelling of the tissue; the diffusivity D also increases with increasingwater content. Thus, the net result of a change in stratum corneumhydration on TEWL is not always predictable. However, in healthy skin, Dusually predominates and TEWL increases.

The introduction of the partition coefficient K_(m) into equation 1takes account of the fact that in the diffusion process theconcentrations at the surfaces of the membrane are not necessarily equalto the concentrations in the external solutions. K_(m) is defined asK_(m)=c_(m)/c_(s), where c_(m)=concentration of H₂O in the membrane (gH₂O cm⁻³ of wet tissue); and c_(s)=concentration of H₂O in the solution(g H₂O cm⁻³ of solution). Blank et al. (1984) J. Invest. Dermatol. 188.

It is an objective of the present invention to provide a compound thatis capable of conferring a long-lasting skin care benefit. Currentlyavailable skin care products do not offer the convenient, long-termeffects of the present invention. It is a further object of the presentinvention to provide a long-lasting compound that can be used intreating and preventing a dry skin condition, strengthening skin, orproviding protection against UV light, for example by inducing anucleophilic addition reaction to occur between the skin and the agentthat provides these emolliency, moisturizing, strengthening orUV-protective effects. As a result, the agent is covalently bonded toskin proteins. Because new cells are continually being produced from thestratum basale to be shed, eventually, from the surface the bindingperiod may last for possibly weeks to maintain the hydration andstrengthening of the skin. Periodic application of the agent affords avirtually continuous maintenance of the beneficial effects, as themodified proteins work their way to the surface and reside in all theupper layers.

SUMMARY OF INVENTION

The present invention provides compounds that comprise at least onebonding agent and at least one characteristic use agent. The bondingagent is a chemical moiety which is capable of covalently bonding to oneor more proteins in skin. The characteristic use agent is a chemicalmoiety which is capable of providing a skin care benefit. Skin carebenefit, as used herein, means a cosmetic effect imparted by aparticular characteristic use agent, such as but not limited to, theability to provide emolliency, moisturing effect, or skin protectanteffect, etc.

In certain embodiments, the bonding agent is selected from the groupconsisting of a crotonyl thiol ester, a sorbyl thiol ester or any othersuitable α,β-unsaturated ester or thiol ester, and mixtures thereof; andthe characteristic use agent is selected from the group consisting ofemollients and skin soothing agents, moisturizers, sunscreens,insecticides, antibacterial agents, fungicides, antiviral agents, skinlightening agents, anti-acne agents, artificial tanning agents,free-radical scavengers, antioxidants, and mixtures thereof.

In a further embodiment the characteristic use agent can be connected tothe bonding agent by a labile or cleavable linkage, resulting in a slowor long-term release of the characteristic use agent into the skin.

Exemplary compounds include octadecyl S-sorbyl-3-mercaptopropionate(hereinafter “OSM”), octadecyl S-crotonyl 3-mercaptopropionate(hereinafter “OCM”), S-crotonyl-ω-mercapto[poly(ethylene glycol)](hereinafter “CPEG”), S,S′-dicrotonyl-α-thio-ω-mercapto[poly(ethyleneglycol)] (hereinafter “DCPEG”), S-sorbyl-ω-mercapto[poly(ethyleneglycol)] (hereinafter “SPEG”), andS,S′-disorbyl-α-thio-ω-mercapto[poly(ethylene glycol)] (hereinafter“DSPEG”), S-crotonyl-2-mercaptoethyl 4-methoxycinnamate (hereinafter“CMC”), and S-sorbyl-2-mercaptoethyl 4-methoxycinnamate (hereinafter“SMC”).

The present invention further provides compositions comprising thecompounds of the present invention and a cosmetically acceptablecarrier. The present invention also encompasses methods of conferring askin care benefit by applying to mammalian skin the compounds andcompositions containing compounds of the present invention.

In an alternate embodiment one or more characteristic use agents can bebound to fibers that contain, or have been modified to contain, asuitable nucleophilic group that can react with the bonding agent.

The present compounds and compositions impart long-lasting skin carebenefits, e.g., suppleness, emolliency and moisturizing effects, to skinand hair. The bonding agent is capable of covalently bonding to proteinsin skin, thereby maintaining the characteristic use agent effects forpossibly weeks by preventing loss of the characteristic use agents(e.g., by washing). Thus, the compounds and compositions containing thecompounds of the invention help skin to resist the irritating effects ofsubstances that remove skin lipids, such as detergents and organicsolvents, help to resist the drying effect that results from skinexposure to the environment, or provide long-term sunscreen protection,depending upon the particular characteristic use agent present in thecompound.

DESCRIPTION OF THE DRAWING

FIG. 1 is a diagrammatic illustration showing the anatomy of human skinincluding the sulfhydryl-rich region.

DETAILED DESCRIPTION OF INVENTION

The present invention provides compounds that are two part moleculescomprising a bonding agent and a characteristic use agent.

The compounds of the present invention have the generic formula

wherein each y is independently 1 or 2. The crotonyl thiol ester orsorbyl thiol ester moiety

is the bonding agent and “X” is the characteristic use agent.

The characteristic use agent is selected from the group consisting ofemollients and skin soothing agents, moisturizers, sunscreens,insecticides, antibacterial agents, fungicides, skin lightening agents,antiviral agents, anti-acne agents, artificial tanning agents,free-radical scavengers, antioxidants, and mixtures thereof. Suitablecharacteristic use agents, for use herein, can be found in the CTFACosmetic Ingredient Dictionary (3^(rd) ed., 1982) and the CTFA CosmeticIngredient Handbook, (2nd ed., 1992), both published by The Cosmetic,Toiletry & Fragrance Association, Inc., which references areincorporated herein by reference in their entirety.

Emollients and skin soothing agents are known in the art and include,for example, oils, petrolatum, lanolin, fatty acids, fatty alcohols,triglyceride esters, wax esters, and esters of polyhydric alcohols.Suitable emollients and oils are disclosed by Idson (1992) Cosm. &Toil., 107:69 and U.S. Pat. No. 5,607,980, incorporated herein byreference. Skin soothing agents include bisabolol and non-steroidal,anti-inflammatory actives (NSAIDS) such as anesthetics. Examples ofNSAIDS include propionic acid derivatives; acetic acid derivatives;fenamic acid derivatives biphenylcarboxylic acid derivatives; andoxicams. All of these NSAIDS are fully described in U.S. Pat. No.4,985,459 to Sunshine et al., issued Jan. 15, 1991, incorporated byreference herein in its entirety. Examples of specific NSAIDS includeacetyl salicylic acid, ibuprofen, naproxen, benoxaprofen, flurbioprofen,fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen,oxaprozin, pranoprofen, microprofen, tioxaprofen, suprofen,alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid. Also usefulare the steroidal anti-inflammatory drugs including hydrocortisone andthe like.

Examples of topical anesthetic drugs include benzocaine, lidocaine,buviacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine,tetracaine, dyclonine, hexyclaine, procaine, cocaine, ketamine,pramoxine, phenol, and pharmaceutically acceptable salts thereof.

Moisturizers or humectants are known in the art and include, forexample, materials selected from the group consisting of glycerol;guanidine; glycolic acid and glycolate salts (e.g., ammonium andquaternary alkyl ammonium); lactic acid and lactate salts (e.g.,ammonium and quaternary alkyl ammonium); aloe vera in any of its varietyof forms (e.g., aloe vera gel); polyhydroxy alcohols such as sorbitol,glycerol, hexanetriol, propylene glycol, butylene glycol, hexyleneglycol and the like; polyethylene glycols; sugars and starches includingsorbitol; sugars and starch derivatives (e.g., alkoxylated glucose);hyaluronic acid; pyrrolidone carboxylic acid; lactamidemonoethanolamine; acetamide monoethanolamine; and mixtures thereof.

Also, useful are propoxylated glycerols as described in U.S. Pat. No.4,976,953, to Orr et al., issued Dec. 11, 1990, which is incorporated byreference herein in its entirety. Suitable moisturizers are alsodisclosed by Loden et al. (1994), “Product Testing—Testing ofMoisturizers,” in Bioengineering of the Skin: Water and the StratumCorneum, Elsner et al., eds, CRC Press, Boca Raton, Fla., 275.

Skin protecting agents are known in the art and are useful herein as acharacteristic use agent and include sunscreens, insecticides, insectrepellants, anti-acne additives, anti-wrinkle and anti-skin atrophyadditives.

A wide variety of sunscreening agents are described in U.S. Pat. No.5,087,445, to Haffey et al., issued Feb. 11, 1992; U.S. Pat. No.5,073,372, to Turner et al., issued Dec. 17, 1991; U.S. Pat. No.5,073,371, to Turner et al., issued Dec. 17, 1991; and Segarin, et al.,at Chapter VIII, pages 189 et seq., of Cosmetic Science and Technology,all of which are incorporated herein by reference in their entirety.Nonlimiting examples of sunscreens which are useful in the compositionsof the present invention are those selected from the group consisting of2-ethylhexyl p-methoxycinnamate, 2-ethylhexylN,N-dimethyl-p-aminobenzoate, p-aminobenzoic acid,2-phenylbenzimidazole-5-sulfonic acid, octocrylene, oxybenzone,homomenthyl salicylate, octyl salicylate,4,4′-methoxy-t-butyldibenzoylmethane, 4-isopropy dibenzoylmethane,3-benzylidene camphor, 3-(4-methylbenzylidene) camphor, anthanilates,ultrafine titanium dioxide, zinc oxide, silica and iron oxide andmixtures thereof. Still other useful sunscreens are those disclosed inU.S. Pat. No. 4,937,370, to Sabatelli, issued Jun. 26, 1990; and U.S.Pat. No. 4,999,186, to Sabatelli et al., issued Mar. 12, 1991; these tworeferences are incorporated by reference herein in their entirety. Thesunscreening agents disclosed therein have, in a single molecule, twodistinct chromophore moieties which exhibit different ultravioletradiation absorption spectra. One of the chromophore moieties absorbspredominantly in the UVB radiation range and the other absorbs stronglyin the UVA radiation range. These sunscreening agents provide higherefficacy, broader UV absorption, lower skin penetration and longerlasting efficacy relative to conventional sunscreens. Examples of thesesunscreens include those selected from the group consisting of4-N,N-(2ethylhexyl)methylaminobenzoic acid ester of2,4-dihydroxybenzophenone, 4-N,N-(2-ethylhexyl)-methylaminobenzoic acidester with 4-hydroxydibenzoylmethane,4-N,N-(2-ethylhexyl)-methylaminobenzoic acid ester of2-hydroxy-4-(2-hydroxyethoxy)benzophenone,4-N,N(2-ethylhexyl)-methylaminobenzoic acid ester of4-(2-hydroxyethoxy)dibenzoylmethane, and mixtures thereof.

Nonlimiting examples of anti wrinkle and anti-skin atrophy activesinclude retinoic acid and its derivatives (e.g., cis and trans);retinol, retinyl esters, salicylic acid and derivatives thereof;sulfur-containing D and L amino acids other than cysteine and theirderivatives and salts, particularly the N-acetyl derivatives;alpha-hydroxy acids, e.g., glycolic acid, and lactic acid; phytic acid,lipoic acid, lysophosphatidic acid, and skin peel agents (e.g., phenoland the like).

Nonlimiting examples of insecticides, insect repellants andanti-arthropod agents include N,N-diethyl-m-toluamide, N-aryl andN-cycloalkyl neoalkonamide compounds as desecribed in U.S. Pat. No.5,434,190 incorporated by reference herein, terpenoids, especiallyterpenoid alcohols and terpenoid-esters, aldehyde and ketones ofterpenes as described in U.S. Pat. No. 5,411,992 incorporated byreference herein, oils of citronella, cedar and wintergreen as describedin U.S. Pat. No. 5,106,622 incorporated by reference herein,1-nonen-3-ol, and pyrethrum/pyrethoids as described in U.S. Pat. No.4,668,666 incorporated by reference herein.

Antibacterial agents such as antibiotics and bactericides, andfungicides are known in the art and are useful herein as acharacteristic use agent. Nonlimiting examples of useful antibacterialagents and fungicides include, β-lactam drugs, quinolone drugs,ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin,2,4,4′-trichloro-2′-hydroxy diphenyl ether, 3,4,4′-trichlorobanilide,phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycycline,capreomycin, chlorhexidine, chloretracycline, oxytetracycline,clindamycin, ethambutol, hexamidine isethionate, metronidazole,pentamidine, gentamicin, kanamycin, lineomycin, methacycline,methenamine, minocycline, neomycin, netilmicin, paromomycin,streptomycin, tobramycin, miconazole, tetracycline hydrochloride,erythromycin, zinc erythromycin, erythromycin estolate, erythromycinstearate, amikacin sulfate, doxycycline hydrochloride, capreomycinsulfate, chlorhexidine gluconate, chlorhexidine hydrochloride,chlortetracycline, hydrochloride, oxytetracycline hydrochloride,clindamycin hydrochloride, ethambutol hydrochloride, metronidazolehydrochloride, pentamidine hydrochloride, gentamicin sulfate, kanamcyinsulfate, lineomycin hydrochloride, methacycline hydrochloride,methenamine hippurate, methenamine mendelate, minocycline hydrochloride,neomycin sulfate, netilmicin sulfate, paromomycin sulfate, streptomycinsulfate, tobramycin sulfate, miconazole hydrochloride, amanfadinehydrochloride, amanfadine sulfate, octopirox, parachlorometa xyleneol,nystatin, tolnaftate and clotrimazole.

Skin lightening agents are known in the art and are useful herein as acharacteristic use agent. Nonlimiting examples of useful skin lighteningagents include glycosides of hydroxysalicylic acid and/or the glycosidesof aliphatic esters of hydroxysalicylic acid as described in U.S. Pat.No. 5,700,784 incorporated by reference herein, hydroquinone, kojic acidor a derivative thereof, especially the salts or esters thereof asdescribed in U.S. Pat. No. 5,279,834 incorporated by reference herein,3-hydroxy-4(H)-pyran-4-one and its 3-acyl derivatives as described inU.S. Pat. No. 4,545,982 incorporated by reference herein, and4-hydroxy-5-methyl-3[2H]-furanone.

Artificial tanning agents and accelerators are known in the art and areuseful herein as a characteristic use agent. Nonlimiting examples ofuseful artificial tanning agents and accelerators includedihydroxyacetone, tyrosine, tyrosine esters such as ethyl tyrosinate,and phospho-DOPA.

Anti-Acne Actives are known in the art and are useful herein as acharacteristic use agent. Nonlimiting examples of useful anti-acneactives include the keratolytics such as salicylic acid(o-hydroxy-benzoic acid), derivatives of salicylic acid such as5-octanoyl salicylic acid, and resorcinol; retinoids such as retinoicacid and its derivatives (e.g., cis and trans); sulfur-containing D andL amino acids other than cysteine and their derivatives and salts,particularly their N-acetyl derivatives; lipoic acid; antibiotics andantimicrobials such as benzoyl peroxide, octopirox, tetracycline,2,4,4′-trichloro-2′-hydroxydiphenyl ether, 3,4,4′-trichlorobanilide,azelaic acid and its derivatives, phenoxyethanol, phenoxypropanol,phenoxisopropanol, ethyl acetate, clindamycin and melclocycline;sebostats such as flavonoids; and bile salts such as scymnol sulfate andits derivatives, deoxycholate, and cholate.

Antiviral agents are also known in the art and useful herein as acharacteristic use agent. Nonlimiting examples of antiviral agentsinclude acyclovir, vidarabine, penciclovir, trifluridine, idoxuridine,podophyllotoxin and carbenoxolone.

Free radical scavengers and antioxidants are known in the art and areuseful herein as a characteristic use agent. Nonlimiting examples ofuseful free-radical scavengers and antioxidants include butylatedhydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherols andtheir derivatives, ascorbic acid, its salts, derivatives such asascorbyl palmitate and their salts, retinol and related carotenoids,bioflavonoids such as hesperitin, naringen, rutin, and quercetin,indole-3-carbinol, pycnogenol, melatonin, sulforaphane, pregnenolone,lipoic acid, amide and derivatives, 4-hydroxy-5-methyl-3[2H]-furanone,ferruginol type compounds as described in U.S. Pat. No. 5,552,158 andesters of cinnamic acid as described in U.S. Pat. No. 5,536,500, Galeyincorporated by reference herein.

The aforementioned characteristic use agents can bound to fibers andother insoluble substrates as described in WO 98/18447 which eithercontain, or have been modified to contain, a nucleophilic group whichcan react with the bonding agent.

The compounds of the present invention may be synthesized by applicationof known organic chemical synthetic methods. Exemplary compounds includethe following:

wherein n is primarily 8 to 9;

wherein n is primarily 7 to 8;

wherein n is primarily 8 to 9;

wherein m is primarily 7 to 8;

The compounds of the present invention covalently bond to skin by areaction of the bonding agent of the present compounds with anucleophilic group (Nu⁻) of a skin protein without requiring an enzymeto catalyze the reaction. As used herein, the designation Nu⁻ refers tonucleophilic groups contained in the skin including but not limited tosulfhydryl groups of cysteine residues, both in the neutral (—SH) andionized forms (—S⁻), including cysteine residues formed in situ byreduction of skin cystine residues, the —NH₂ of lysine residues and theN-terminus of proteins, the imidazole side chain of histidine residues,and the hydroxyl group of tyrosine residues, both in the neutral (—OH)and ionized (—O⁻) forms.

The skin is rich in these nucleophilic groups. Free —SH residues ofproteins are concentrated in the cell membrane or intracellular spacesin the junctional zone of living keratinocytes and the dead horny layerof human epidermis. The stratum spinosum-stratum granulosum boundary isrich in the neutral (—SH) and ionized (—S⁻) forms of sulfhydryl groupsof cysteine, shown diagramatically in FIG. 1. In the horny layer, thedistribution of —SH groups is moderately high in the mid-stratumcorneum, and then decrease gradually on the way up to the surface of theskin. Ogawa et al. (1979) J. Histochem. Cytochem. 27:942.

The reactivities of the compounds of the present invention are optimalin that the compounds are not so reactive as to induce skin irritation,nor damage essential biomolecules, nor produce harmful byproducts,whereas the compounds have sufficient reactivity to undergo reactionwith skin nucleophiles (e.g. —S⁻) under relatively mild conditions. Theinvention employs a novel kind of reaction, namely the conjugateaddition reaction, in which nucleophiles attack a C═C that is conjugatedto a thiol ester functional group. The addition reaction does notproduce any by-products, as would have been generated by a nucleophilicsubstitution reaction (e.g., Nu⁻R—X-Nu-R+X⁻, where X⁻ is a potentiallyundesirable by-product). The other novel aspect of the present compoundsis the use of a thiol ester group, because it enhances the reactivity ofthe C═C that it is conjugated to more than an ordinary ester group does.Thus, for example, the α,β,γ,δ-unsaturated thiol ester group of OSM[C—C═C—C═C—C(═O)—S—R] and the α,β-unsaturated thiol ester groups of OCM,CPEG and CMC [C—C═C—C(═O)—S—R] are novel groups that are ideally suitedfor the desired reaction with skin nucleophiles.

To enhance the reaction between the present compounds and skinnucleophiles, a base, such as bicarbonate or triethanolamine, may beused in combination with the present compounds to convert the lessnucleophilic —SH groups into the more nucleophilic —S groups. The baseconverts some weak nucleophiles into strong nucleophiles (e.g., —SH into—S⁻, tyrosine's —OH into —O⁻, and reveals —NH₂ from the nonnucleophilic—NH₃ ⁻ form).

Exemplary compounds of the present invention include OSM, OCM, CPEG,DCPEG, SPEG, DSPEG, CMC and SMC. The compound OSM consists of a two-partmolecule. One part is designed to impart emolliency/moisturizing effectsto skin, whereas the other part is designed to become covalently bondedto skin. An illustrative method of synthesizing OSM is provided atExample 1 hereinbelow. The part of the molecule designed to react withskin can do so with two different skin protein molecules or differentregions of the same molecule, thereby crosslinking skin and adding tothe skin's strength, and thus providing an important benefit for elderlyindividuals, who often have fragile, easily torn skin.

The covalent bonding of OSM to skin is based upon the nucleophilicattack of Nu⁻ groups in skin. A representative chemical reaction is asfollows:

in which Nu⁻ in the chemical equation is as defined hereinabove. Thischemical reaction describes one of the ways covalent attachment of OSMto skin can occur in water, although other solvents and other modes ofcovalent attachment are possible.

As a model for skin-bound sulfhydryl groups (—SH) of cysteine residuesin skin proteins, the compound N-acetylcysteamine was allowed to reactwith OSM in the presence of a catalytic amount of the base1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in chloroform solution. Theaddition of N-acetylcysteamine to OSM, in a manner that is expected toparallel the addition of skin-bound nucleophiles (e.g., cysteineresidues in skin proteins) to OSM, showed that covalent bond formationoccurred, giving the compound shown below, or a related adduct.

Covalent attachment also occurs between OSM and cysteine ethyl ester,another model for skin-bound cysteine residues in skin proteins, undersimilar conditions. The addition of cysteine ethyl ester to OSM in amanner that is expected to parallel the addition of skin-boundnucleophiles (e.g., cysteine residues of skin proteins) to OSM isthought to occur as shown below, or by a similar adduct formation path.

In the case of skin nucleophiles, the reaction shown below or ananalogous adduct formation is expected to occur, in which a skin-boundsulfhydryl group (here illustrated with a cysteine sulfhydryl group) isthe nucleophile illustrated to react with OSM.

The compound OCM consists of a two-part molecule. One part is designedto impart emolliency/moisturizing effects to skin, whereas the otherpart is designed to become covalently bonded to skin. An illustrativemethod of synthesizing OCM is provided at Example 2 hereinbelow.

The covalent bonding of OCM to skin is based on the nucleophilic attackof Nu⁻ groups in skin. A representative chemical reaction is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofOCM to skin can occur in water, although other solvents and other modesof covalent attachment are possible.

As a model for skin-bound sulfhydryl groups (—SH) of cysteine residuesin skin proteins, the compound N-acetylcysteamine was allowed to reactwith OCM in the presence of a catalytic amount of the base1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in chloroform solution. Theaddition of N-acetylcysteamine to OCM, in a manner that is expected toparallel the addition of skin-bound nucleophiles (e.g., cysteineresidues in skin proteins) to OCM, showed that covalent bond formationoccurred, giving the compound shown below, or a related adduct.

The reaction also occurred between OCM and cysteine ethyl ester, anothermodel for skin-bound cysteine residues in skin proteins, under similarconditions. Addition of cysteine ethyl ester to OCM in a manner that isexpected to parallel the addition of skin-bound nucleophiles (e.g.,cysteine residues in the skin proteins) to OCM is thought to occur asshown below, or by a similar adduct formation path:

In the case of skin, the addition of skin-bound nucleophiles is expectedto occur as shown below or as an analogous adduct formation, in which askin-bound sulfhydryl group is the nucleophile illustrated to react withthe OCM.

Exposure of skin to the environment or removal of skin lipids bydetergents and organic solvents results in a skin-drying effect andirritation. The OSM and OCM molecules have lipid-like characteristics,principally due to the (CH₂)₁₇CH₃ group, that combat the drying effectand irritancy that the loss of skin lipids induces. Because of thecovalent attachment of the lipid-like group to skin components such asproteins, which are not readily removed by detergents and organicsolvents, the lipid-like portion resists removal by detergents andorganic-solvents, and imparts a protective effect to skin exposed tothese agents.

To the extent that the binding of OSM and OCM to skin occurs at thedeeper layers, e.g., the spinosum-granulosum boundary, over time theselayers that contain the bound lipid-like group of OSM and OCM willevolve to the surface layers of the skin, through normal growth processof the skin. This may produce an even more beneficial protective effecton the skin, because the lipid-like bound groups will be in an outerlayer of the skin. Thus, the repeated application of OSM and OCM to skinmight result, over a period of time, in virtually all layers of skinfrom relatively deep (e.g., spinosum-granulosum boundary) to the surface(e.g., stratum corneum) being chemically modified with the lipid-likechains of OSM or OCM.

Besides imparting chemical resistance and long-termemolliency/moisturizing effects to skin, the compounds of the inventionmay impart a skin-strengthening effect. This is a consequence of thepotential of OSM to crosslink skin components, for example to linktogether different protein molecules in skin or different parts of thesame protein molecule in skin. The potential beneficial effect of thisis the strengthening effect that crosslinking has on polymers, such asskin proteins. Thus, for the elderly, who typically have easily torn andinjured skin, the application of OSM might result in a strengthening ofthe skin and a decreased propensity for skin injury. As described above,this effect might increase over time, with repeated application of theinvention, as the lower layers of the skin bearing the crosslinkedprotein molecules evolve to the surface of the skin.

In addition to the uses described above, suitable sorbate thiol estersand crotonate thiol esters of a design apparent to those skilled in theart, having regard for this disclosure, have utility in the extendedprotection of skin, hair, nails, wool, and fur (e.g., from ultravioletlight, by incorporation of sunscreens into the thiol ester; from toxicand/or irritating substances, such as urushiol or urinary by-products;or from insects and parasites, by incorporation of insecticides and/orinsect repellants), dyeing of hair, skin (e.g., tanning or marking, aswith reflectant or colored substances), nails, wool, fur, and othersubstances with native nucleophilic groups or nucleophilic groups thatcan be added or revealed by suitable chemical and/or physicaltreatments.

The compounds CPEG, DCPEG, SPEG and DSPEG are two part molecules. Onepart is designed to become covalently bonded to skin, whereas the otherpart is designed to impart moisturizing effects or humectancy to theskin. Similar compounds that would accomplish substantially the sameresults are readily apparent to one skilled in the art, having regardfor this disclosure. An illustrative method of synthesizing DCPEG isprovided at Example 3 herein below.

As a model for skin bound sulfhydryl groups (—SH) of cysteine residuesin skin proteins, the compound N-acetylcysteamine was allowed to reactwith DCPEG in the presence of a catalytic amount of the base1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in chloroform solution. Theaddition of N-acetylcysteamine to DCPEG in a manner that is expected toparallel the addition of skin-bound nucleophiles (e.g., cysteineresidues in skin proteins) to DCPEG, showed that covalent bond formationoccurred, giving the compound shown below, or a related adduct.

The covalent bonding of CPEG, DCPEG, SPEG, and DSPEG to skin is basedupon the nucleophilic attack of Nu⁻ groups in skin. A representativechemical reaction using CPEG is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofCPEG to skin can occur in water, although other solvents and other modesof covalent attachment are possible. A representative chemical reactionusing DCPEG is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofDCPEG to skin can occur in water, although other solvents and othermodes of covalent attachment are possible. In this case, two skin-boundnucleophiles can become attached to one DCPEG molecule resulting incross-linking of skin. This has the beneficial effect of strengtheningskin, such as the fragile skin of the elderly.

A representative chemical reaction using SPEG is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofSPEG to skin can occur in water, although other solvents and other modesof covalent attachment are possible. Both of the reactive sites on SPEGneed not necessarily react with skin nucleophiles for there to be abeneficial effect on skin.

A representative chemical reaction using DSPEG is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofDSPEG to skin can occur in water, although other solvents and othermodes of covalent attachment are possible. DSPEG can cross-link skin viathe nucleophiles. However, not all four of the reactive sites of DSPEGneed necessarily react with skin nucleophiles in order for there to be abeneficial effect on skin.

To enhance the reaction between CPEG, DCPEG, SPEG and DSPEG with skinnucleophiles, a base may be used in combination with CPEG, DCPEG, SPEGand DSPEG to convert the less nucleophilic —SH groups into the morenucleophilic —S⁻ groups. The base converts some weak nucleophiles intostrong nucleophiles (e.g., —SH into —S⁻, tyrosine's —OH into —O⁻, andreveals —NH₂ from the nonnucleophilic —NH₃ ⁺ form).

For example, in the case of skin nucleophiles, the reaction shown belowor an analogous adduct formation is expected to occur, in which askin-bound sulfhydryl group is the nucleophile illustrated to react withthe CPEG:

Loss of skin moisture through the action of detergents and organicsolvents or exposure to the environment results in a skin drying effect(e.g., flaking) and irritation or aged appearance. The CPEG, DCPEG, SPEGand DSPEG molecules have a humectant or hydrophilic chain derived frompoly(ethylene glycol) that resists the loss of skin moisture and assiststhe accumulation of moisture by the skin, i.e., rehydration of skin,thereby combating the irritancy and other effects that drying induces.The humectancy is presumably derived from the polyether chain(—CH₂CH₂—O—) augmented by the terminal hydroxyl group in the cases ofCPEG and SPEG. Because of the covalent attachment of the hydrophilic,moisture-holding group to the skin components such as proteins, whichare not readily removed by detergents and organic solvents, a protectiveand restorative effect is imparted to skin exposed to these agents.

To the extent that the binding of one or more of CPEG, DCPEG, SPEG, andDSPEG to skin occurs at the deeper layers, e.g., the spinosum-granulosumboundary, over time these layers that contain one or more of the boundhumectant group of CPEG, DCPEG, SPEG, and DSPEG will evolve to thesurface layers of the skin though the normal growth processes of theskin. This may produce an even more beneficial protective effect on theskin, because the bound humectant groups will be in an outer layer ofthe skin. Thus, the repeated application of one or more of CPEG, DCPEG,SPEG, and DSPEG to skin might result, over a period of time, invirtually all layers of skin from relatively deep (e.g.spinosum-granulosum boundary) to the surface (e.g., stratum corneum)being chemically modified with the humectant part of CPEG. DCPEG, SPEG,and DSPEG.

The compounds CMC and SMC are two part molecules. One part is designedto become covalently bonded to skin, whereas the other part is designedto act as a sunscreen and impart protection to the skin against theharmful effects of exposure to ultraviolet light. Similar compounds thatwould accomplish substantially the same results are readily apparent toone skilled in the art, having regard for this disclosure.

French Patent No. 2,566,400, incorporated here by reference, describesthe production of sulfur containing p-methoxycinnamates for use assunscreens. The addition of a bonding agent as described by thisinvention forms CMC or SMC.

An illustrative method of synthesizing CMC is as follows.

Similarly, an illustrative method of synthesizing SMC is as follows.

The covalent bonding of CMC and SMC to skin is based on the nucleophilicattack of Nu⁻ groups in skin. A representative chemical reaction usingCMC is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofCMC to skin can occur in water, although other solvents and other modesof covalent attachment are possible.

A representative chemical reaction using SMC is as follows:

in which the Nu⁻ in the chemical equation is as defined hereinabove.This chemical reaction describes one of the ways covalent attachment ofSMC to skin can occur in water, although other solvents and other modesof covalent attachment are possible. Both of the reactive sites of SMCneed not necessarily react with the skin nucleophiles for there to be abeneficial effect on skin.

To enhance the reaction between CMC and SMC with skin nucleophiles, abase may be used in combination with CMC and SMC to convert the lessnucleophilic —SH groups into the more nucleophilic —S⁻ groups. The baseconverts some weak nucleophiles into strong nucleophiles (e.g., —SH into—S⁻, tyrosine's —OH into —O⁻, and reveals —NH₂ from the nonnucleophilic—NH₃ form).

For example, in the case of skin nucleophiles, the reaction shown belowor an analogous adduct formation is expected to occur, in which a skinbound sulfhydryl group is the nucleophile illustrated to react with theCMC:

A similar reaction or formation of an analogous adduct would occur inthe case of skin nucleophiles and SMC.

Exposure of the skin to ultraviolet light has been implicated as apossible factor in the induction of a number of harmful biologicaleffects, such as skin aging and cancer. The CMC and SMC molecules havean ultraviolet light-absorbing group (4-methoxycinnamate) that impartsprotection from effects of ultraviolet exposure. Because the ultravioletlight-absorbing group is covalently attached via the bonding agent toskin components, such as proteins which are not readily removed bydetergents and organic solvents or exposure to the environment (e.g,water, wind, and abrasion), the ultraviolet light-absorbing portionresists removal by these agents.

To the extent that the binding of one or more of CMC and SMC to skinoccurs at the deeper layers, e.g., the spinosum-granulosum boundary,over time these layers that contain one or more of the bound ultravioletlight-absorbing group of SMC and CMC will evolve to the surface layersof the skin though the normal growth processes of the skin. This mayproduce an even more beneficial protective effect on the skin, becausethe ultraviolet light absorbing groups will be in an outer layer of theskin. Thus, the repeated application of one or more of CMC and SMC toskin might result, over a period of time, in virtually all layers ofskin from relatively deep (e.g. spinosum-granulosum boundary) to thesurface (e.g., stratum corneum) being chemically modified with theultraviolet light-absorbing sunscreen group of CMC and SMC.

From the foregoing it becomes readily apparent new and usefullong-acting, chemical-resistant skin emollients, moisturizers,sunscreens and strengtheners and their preparations have been hereindescribed and illustrated which fulfill all of the aforestatedobjectives. It is of course understood that such modifications,alterations and adaptations as will readily occur to the artisanconfronted with this disclosure are intended within the scope of theinvention.

The present invention further provides compositions comprising one ormore compounds of the present invention and a cosmetically acceptablecarrier which is compatible with the compound of the invention.Cosmetically acceptable carriers include water, alcohols, oils, andother carriers suitable for dissolving or dispersing the activeingredient. The compositions may further contain additional ingredients,such as fluidity promoters, colorants, perfumes, and the like. Suitablecosmetically acceptable carriers and additional ingredients, for useherein, can be found in the CTFA Cosmetic Ingredient Dictionary (3^(rd)ed., 1982) and the CTFA Cosmetic Ingredient Handbook, (2nd ed., 1992),both published by The Cosmetic, Toiletry & Fragrance Association, Inc.,which references are incorporated herein by reference in their entirety.The compositions are useful for application to the skin or hair asmoisturizers, emollients, sunscreens or skin strengtheners, dependingupon the particular characteristic use agent present in the compound ofthe invention.

Methods for the formulation of cosmetic compounds are well known tothose of skill in the art. The compositions may take a form suitable fortopical application, including for example a lotion, cream, gel, orsolid, e.g. stick form, composition. The cosmetic compositions containthe compound of the invention in an amount that will be dependent uponthe characteristic use agent portion of the two-part compound and theintended use of the composition. The compositions may contain thecompound of the invention in an amount of about 0.1% to 35% by weight ofthe composition. For example, a compound of the present invention inwhich the characteristic use agent is a sunscreen agent will preferablybe present in an amount of 0.1% to 15%, and more preferably 1% to 10% byweight of the composition. A compound of the present invention in whichthe characteristic use agent is an emollient will preferably be presentin an amount of 1% to 35%, and more preferably 5% to 20% by weight ofthe composition. A compound of the present invention in which thecharacteristic use agent is a humectant will preferably be present in anamount of 1% to 20%, and more preferably 5 to 15% by weight of thecomposition. Formulations are described in Examples 4 and 5 hereinbelow.

The following examples serve to further illustrate the presentinvention.

EXAMPLE 1 Synthesis and Characterization of OSM and n-Octadecyl Sorbate(OS)

Material and Methods

All reagents used in the synthesis of the sorbate-based esters and thiolesters were purchased from Aldrich Chemical Co. or Lancaster ChemicalCo., except octadecyl 3-mercaptopropionate was obtained from HampshireChemical Corp. Solvents were distilled prior to use. Evaporation ofsolvents was performed under reduced pressure on a Buchi rotaryevaporator. THF refers to tetrahydrofuran, DBN to1,5-diazabicyclo[4.3.0] non-5-ene and TEA to triethylamine. The THF waspredried by refluxing over sodium and benzophenone until permanentlypurple and distilled under an N₂ atmosphere immediately before use.Analtech silica gel GF (0.25 mm) plates were used for thin-layerchromatography (TLC) and developed with a variety of solvents. Afluorescent indicator or an iodine chamber was employed forvisualization of spots. Preparative silica gel thin layer chromatographyplates (10 cm×20 cm, 1000 microns) were obtained from Analtech.Stationary phases used for gravity column chromatography were Baxter70-230 mesh silica gel (VMR Scientific Co.). Tetramethylsilane andresidual CHCl₃ (7.256 ppm) were used as internal references in allnuclear magnetic resonance measurements, which were determined with aVarian AM 300 Gemini spectrometer. Chemical shifts were recorded in ppm,and peak abbreviations for spin multiplicities are: s, singlet; d,doublet; t, triplet; dd, doublet of doublets; dt, doublet of triplets;m, multiplet; br, broad. Deuteriochloroform was used as an NMR solvent.Confirmation of structural data was given by the 2D COSY experiments.Melting points were measured on a Electrothennal Mel-temp apparatus andare uncorrected.

Time-Course NMR Spectral Study

A solution of octadecyl S-sorbyl-3-mercaptopropionate (10.9 mg, 0.024mmol) in 0.3 mL of CDCl₃ was added to a solution of N-acetylcysteamine(5.2 μL, 0.048 mmol) and DBN (3.1 μL, 0.025 mmol) in 0.3 mL of CDCl₃.The mixture was immediately transferred to an NMR tube and the firstspectrum was recorded at time=0. The reaction solution was allowed tostand at room temperature in the NMR tube for two days, and the courseof the reaction was monitored by periodically recording the ¹H NMRspectrum. A total of ten ¹H NMR experiments were performed at time=0,0.25, 0.5, 1, 1.5, 4.5, 12, 20.5, 26, and 39 hours.

Synthesis

Sorboyl chloride (1). To a 500-mL round-bottom flask containing 110 mLof cyclohexane, 3.85 g of sorbic acid was added at room temperature. Thetemperature was increased to 60° C. and 8.9 mL of thionyl chloride wasadded dropwise over a 1-hour period. The mixture was heated under refluxfor 17 hours, after which the solvent and the unreacted thionyl chloridewere evaporated in vacuo, and the mixture was concentrated to a brownresidue: 4.05 g (90%) yield, ¹H NMR (300 MHz) δ 7.30 and 7.70 (total IH, m, HC═CCOCl), 5.8-6.6 (3H, m, olefinic), and 1.9 (total 3H, d, J=5Hz, CH ₃CH═).

n-Octadecyl sorbate (OS). A solution of 0.9 g (6.9 mmol) of sorboylchloride in 6 mL of THF was added slowly with stirring to a mixture of1.87 g (6.9 mmol) of n-octadecanol in 10 mL of THF at 40° C. Theresulting mixture was refluxed for 16 hours. The solvent was evaporatedunder reduced pressure and the crude product was purified by columnchromatography on silica gel using chloroform as eluent. The appropriatefractions were combined and evaporated to dryness in vacuo to give awhite solid product: 1.04 g (42%) yield. TLC (CHCl₃) R_(f)=0.75. ¹H NMR(300 MHz) δ 0.89 [3H, t, —(CH₃)₁₅CH ₃)], 1.25 [30H, br m, —(CH₃)₁₅—],1.62 [2H, t, —OCH₂CH ₂—], 1.86 [3H, d, CH ₃CH═], 4.14 [2H, t, —OCH₂—],5.79 [1H, d, OCCH═], 6.19 [2H, m, CH₃CH═C—], 7.22 [1H, m, CH₃CH═CH—CH═].

Octadecyl S-sorbyl-3-mercaptopropionate (OSM). To a solution of 11.1 g(31.1 mmol) of octadecyl 3-mercaptopropionate dissolved in 30 mL ofcyclohexane, at 45° C. was slowly added 4.05 g (31.0 mmol) of sorboylchloride in 35 mL of cyclohexane. The resulting mixture was stirred andrefluxed for 15 hours. The solvent was evaporated in vacuo, leaving abrown liquid. The resulting residue was applied to a column of silicagel and product was eluted with 10% ethyl acetate in hexanes solution.The appropriate fractions were combined and concentrated to give a whitesolid: 7.5 g (67%) yield. TLC (ethyl acetate/hexanes [10:90]) R_(f)0.55.¹H NMR (300 MHZ) δ 0.89 [3H, t, —(CH₂)₁₅₋CH ₃], 1.24 [30H, broad m,—(CH₂)₁₅−], 1.61 [2H, t, —OCH₂CH ₂—], 1.94 [3H, d, CH ₃CH═], 2.63 [2H,t, —SCH₂CH ₂—], 3.20 [2H, t, —SCH₂—], 4.08 [2H, t, —OCH₂—], 6.02 [H, d,OCCH═]1, 6.20 [2H, m, CH₃CH═CH—], 7.20 [1H, m, OCCH═CH—].

n-Octadecyl sorbate-N-acetyleysteamine monoadduct (2). To a solution of109 mg (0.30 mmol) of n-octadecyl sorbate dissolved in 6 mL ofcyclohexane/chloroform (50:50) was added 31.9 μL (0.30 mmol) ofN-acetylcysteamine and 18 μL (0.15 mmol) of DBN. The mixture was heatedat reflux for 15 hours, after which the solvent was evaporated in vacuo.The residue was placed onto a column of silica gel and product waseluted with 5% methanol in chloroform. The appropriate fractions werecombined and concentrated to give a colorless oil (0.056 g, 39%). TLC(cyclohexane/chloroform [50:50]) R_(f)=0.66, ¹H NMR (300 MHz) δ 0.89[3H, t, CH ₃CH₂)₁₅—], 1.22 [30H, br m, CH₃(CH ₂)₁₅—], 1.31 [3H, d, CH₃CH(S—)CH₂—, 1.61 [2H, t, —OCH₂CH ₂—], 2.00 (3H, s, acetyl], 2.44-2.72[2H, two dd, —NHCHH′—], 3.16 [2H, d, O═CCH₂—], 3.31-3.42 [3H, m,CH₃CH(SCH ₂—)CH═], 4.08 [2H, t, —OCH₂—], 5.40 [1H, dd, C(3) olefinic],5.55 [1H, dd, C(4) olefinic], 6.02 [1H, br s, amide proton].

Octadecyl S-sorbyl-3-mercaptopropionate-N-acetylcysteamine monoadducts(3 and 4). In a 50-mL round-bottom flask, 181 mg (0.40 mmol) of OSM wasdissolved in 10 mL of chloroform, which was purged with nitrogen for 15minutes prior to use. 30 μL (0.28 mmol) of N-acetylcysteamine and 39 μL(0.28 mmol) of triethylamine were added, and the solution was stirredunder reflux in a nitrogen atmosphere for 2 hours. The solvent wasevaporated and the mixture of monoadducts was isolated by preparativeTLC with 3% methanol in chloroform. Rf=0.66. The isolated monoadductsmixture was spotted onto another preparative TLC plate, and themonoadducts were separated by repetitive developments with 3% methanolin chloroform. ¹H NMR (300 MHz) (monoadduct 3) δ 0.89 [3H, t,—(CH₂)₁₅CH₃], 1.30 (30H, br m, —(CH₂)₁₅—], 1.31 [3H, d, CH ₃CH(S—)CH═],1.61 (2H, t, —OCH₂CH ₂—), 2.00 (3H, s, acetyl], 2.55 [1H, m,—NHCH₂CHH′—], 2.62 [2H, t,OC(O)CH₂], 2.65 [1H, m, —NHCH₂CHH′—], 3.12[2H, t, O═CSCH₂—], 3.32 [3H, m, CH₃CH(SCH₂CH ₂)CH═], 3.29 [2H, d,—SC(O)CH₂—], 4.10 [2H, t, —OCH ₂(CH₂)₁₆—], 5.42-5.62 [2H, m, olefinic],6.00 [1H, br s, amide proton]. COSY Correlations: δ 0.89/1.30,1.30/1.61, 1.31/3.44, 1.61/4.10, 2.55/2.65, 2.62/3.12, 3.29/5.52,3.32/5.35, 5.35/5.52. ¹H NMR(300 MHz) (monoadduct 4) δ 0.89 [3H,t,—(CH₂)₁₅CH ₃], 1.30 [30H, br m, —CH₂)₁₅—], 1.61 [2H, t, —OCH₂CH ₂—],1.71 (3H, d, CH ₃CH═], 2.00 [3H, s, acetyl], 2.55 [1H, m, —SCHH′CH₂NH—],2.65 [1H, m, —SCHH′CH₂NH—], 2.61 [2H, t, —OC(O)CH₂—], 2.79[2H d,—SC(O)CH₂—], 3.18 [2H, t, O═CSCH₂—), 3.40 [1H, dt, —NHCHH′—], 3.42 [1H,dt, —NHCHH′—], 3.63 [1H, m, CH₃CH═CHCH(S—)CH₂—], 4.08 [2H, t, —OCH₂(CH₂)₁₆—], 5.28 [1H, m, C(4) olefinic], 5.55 [1H, m, C(5) olefinic],6.00 [1H, br s, amide proton]. COSY correlations: δ 0.89/1.30,1/30/1.61, 1.61/4.10, 1.71/5.55, 2.55/2.65, 2.61/3.18,2.55-2.65/3.40-3.42, 2.79/3.63, 3.40/3.42, 3.63/5.28, 5.28/5.55.

Reaction By-Products Formation.

To a 25-mL round-bottom flask equipped with a drying tube, 45.2 mg (0.10mmol) of OSM, 21.3 μL (0.20 mmol) of N-acetylcysteamine and 12.3 μL(0.10 mmol) of DBN were dissolved in 5 mL of CHCl₃. The reaction mixturewas allowed to stir at room temperature for 6 hours and was periodicallymonitored by TLC (ethyl acetate/hexanes [50:50]) for the disappearanceof starting material. The solvent was evaporated under reduced pressureand the reaction crude mixture was purified by column chromatography onsilica gel using 3% hexanes in methylene chloride solution. The isolatedproducts were individually identified by NMR spectroscopy and theirspectral data were summarized as follows:

Bis(octadecyl 3-mercaptopropionyl)disulfide (6). TLC (ethylacetate/hexanes [50:50]) Rf=0.93. 1H NMR (300 MHz) δ 0.89 [6H, t,methyl], 1.23 [60H, br m, —(CH₂)₁₅—], 1.61 [4H, t, —OCH₂CH ₂—], 2.72[4H, t, —SCH₂CH ₂—], 2.94 [4H, t, —SCH₂—], 4.09 [4H, t, —OCH₂—].

N-Acetylcysteamino octadecyl 3-mercaptopropionyl disulfide (7). TLC(ethyl acetate/hexanes [50:50]) Rf=0.67, ¹H NMR (300 MHz) δ 0.89 [3H, t,methyl], 1.25 [30H, br m, —(CH₂)₁₅—], 1.62 [2H, t —OCH₂CH ₂—], 2.00 [3H,s, acetyl], 2.74 [2H, t, —OC(O)CH₂—], 2.81 [2H, t, —NHCH₂CH ₂—], 2.94[2H, t, —OC(O)CH ₂CH₂—], 3.60 [2H, q, —NHCH ₂—], 5.89 [1H, br s, amideproton].

S-sorbyl 2-mercapto(N-acetyl)ethylamine (8). TLC (ethyl acetate/hexanes[50:50]) Rf=0.48, ¹H NMR (300 MHz) δ 1.87 [3H, d, methyl], 1.99 [3H, s,acetyl], 3.11 [2H, t, —SCH₂—], 3.44 [2H, t, —SCH₂CH ₂—], 5.89 [1H, br s,amide proton], 6.09 [1H, d, OCCH═], 6.21 [2H, m, CH₃CH═CH—], 7.20 (1H,m, CH₃CH═].

As described above, OSM and OS were synthesized via the nucleophilicacyl substitution reaction of the sorboyl chloride with thecorresponding thiol or alcohol, respectively. The route for thepreparation of these compounds is as follows.

Sorboyl chloride was chosen based upon the fact that sorbic acid hasbeen considered to be harmless and is included in the list of GRASchemicals (generally regarded as safe). The preparation of sorboylchloride starting material 1 was achieved by refluxing a cyclohexanesolution of sorbic acid and thionyl chloride according to the procedureof MacMilan et al. (1973) J. Org Chem., 2982, except that the volatileswere removed by rotary evaporation instead of distillation. The yield ofsorboyl chloride (90%) was the same as that reported by MacMilan et al.OS was prepared in 42% yield by treatment of 1 with 1 equiv of n-octanolin THF at reflux for 16 hours as described by Tieke (1995) Colloid Poly.Sci. 236:966. A similar procedure as that used in the preparation of OSwas employed to prepare OSM; treatment of 1 with 1 equiv of octadecyl3-mercaptopropionate in refluxing cyclohexane for 16 hours gave a 67% ofOSM.

The study of the reaction between OSM and OS with the model skinprotein, N-acetylcysteamine, demonstrated that both of the prospectiveemollient agents, OSM and OS, can be attached to the skin covalently viaa nucleophilic addition as follows:

OS was allowed to react with 1 equiv of N-acetylcysteamine in thepresence of 0.5 equiv of the base DBN in refluxingcyclohexane/chloroform mixture; the reaction gave the correspondingmonoadduct 2 in 39% yield. Structural assignment of the monoadduct 2 wasclearly made on the basis of its ¹H NMR spectral data and 2D COSYcorrelations. The formation of the 2,5-addition product was confirmed.

The reaction of OSM with 0.7 equiv of N-acetylcysteamine in the presenceof 0.7 equiv of triethylamine in chloroform at reflux, under an N₂atmosphere, for 2 hours gave a mixture of two isomeric monoadducts, 3and 4. The crude reaction mixture was concentrated to a small volume,which was subjected to column chromatography on silica gel forisolation. The method of column chromatography alone was insufficient toachieve a high level of purification; the two monoadducts elutedtogether. To separate the monoadducts 3 and 4, we employed therepetitive preparative TLC purification procedure. By analogy to thereaction of OS with N-acetylcysteamine, OSM would be expected to givemonoadduct 3. In addition, monoadduct 4 was also obtained.

The ¹H NMR spectra of both of the two monoadducts 3 and 4 exhibited thecorresponding olefinic protons as a pair of multiplets at δ 5.6-5.4 andδ 5.6-5.2, respectively, and no signal assignable to olefinic protons atδ 6.2-6.0 and δ 7.2, attributable to the original dienyl portion of thesorbate group, —CH═CH—CH═CH—. The assignment of the olefinic protonsignals was made on the basis of correlations in the 2D COSY spectra.These correlations indicated that the signals at δ 5.35 and δ 5.52 aredue to the olefinic protons H-3 and H-4 of monoadduct 3; and the signalsat δ 5.28 and δ 5.55 are due to the olefinic protons H-4 and H-5 ofmonoadduct 4. The upfield-shifted olefinic proton signal for C-4 inmonoadduct 3 correlates with the multiplet signal at δ 3.32 for C-5,which in turn correlates with the methyl signal at δ 1.31 for C-6. Themethyl doublet at δ 1.71 for C-6 correlates with the downfield-shiftedolefinic signal at δ 5.55 for C-5 in monoadduct 4; and the aliphaticsignals at δ 3.63 for C-3 correlates with the upfield-shifted olefinicsignal at δ 5.28 for C-4 as well as the doublet at δ 2.79 for C-2. The¹H NMR spectral results, together with the correlations in the 2D COSYspectra, demonstrated that both of the 2,5-addition product, 3, and the2,3-addition product, 4, were formed in the reaction.

The time course of the reaction of OSM with 2 equiv ofN-acetylcysteamine in the presence of 1 equiv of DBN in 0.6 mL of CDCl₃was studied by recording ¹H NMR spectra at various times for 39 hours.The signals of the olefinic protons due to the sorbate group of OSM (δ6.2-6.0 and δ 7.2) and that of the newly formed C═C bond of themonoadducts (δ 5.6-5.2) were monitored in particular. In the course ofthese experiments, it was observed that the signals at δ 6.2-6.0 and δ7.2 disappeared, while those at δ 5.6-5.2 appeared over the first 1.5hours of the reaction, which indicated the formation of the monoadducts.The olefinic protons signals of the monoadducts started to fade awaygradually after 1.5 hours and became very weak by approximately 39hours. These spectra may imply the formation of the diadduct.

Only one monoadduct 2 was isolated in the reaction of OS withN-acetylcysteamine, while two different monoadducts 3 and 4 wereobtained in the reaction of N-acetylcysteamine with OSM. The varyingreactivity of the C═C of the sorbate group of the different agentstowards nucleophilic attack may account for the differences.

When reactions were carried out in the absence of an N₂/inert gasatmosphere, as an attempt to bind together the protein bound sulfhydrylgroups with OSM, a range of side products were isolated by columnchromatography, as shown below.

Two molecules of octadecyl-3-mercaptopropionate were oxidized to form asymmetrical Bis(octadecyl 3-mercaptopropionyl)disulfide 6. Theunsymmetrical N-acetylcysteamino octadecyl 3-mercaptopropionyl disulfide7 was made when one molecule of octadecyl 3-mercaptopropionate and onemolecule of N-acetylcysteamine were oxidized and coupled. The by-productS-sorbyl 2-mercapto(N-acetyl)ethylamine 8 was also obtained in thereaction mixture. It was formed possibly from the attack of the carbonylcarbon of OSM followed by the displacement of the group octadecyl3-mercaptopropionate of OSM by the deprotonated N-acetylcysteaminethiolate anion. In contrast, the formation of the disulfide by-productswas impossible in similar reactions with OS.

The proposed mechanism for the reactions is summarized below.

The nucleophilic attack by the thiolate anion (—RS—) at the δ-carbonatom of the sorbate group of OS or OSM results in an enolateintermediate, which protonates at the C-2 position to give a2,5-addition monoadduct 2 or 3 (route 1). The 2,5-addition monoadducthas a double bond that is not conjugated to the carbonyl group andcannot undergo a further nucleophilic addition reaction to yield thedesired diadduct compound. According to the results of the NMR spectralstudy of the time course of the reaction, the formation of the diadductis of the greatest likelihood. In order to account for the observation,route 2 that leads to the formation of the 4,5-addition monoadductsuggests a better explanation for the possibility of the formation ofthe reaction diadduct. The resulting enolate intermediate protonates atthe C-4 position and forms a monoadduct that has a double bond that isconjugated to the carbonyl group and is capable of reacting further in anucleophilic reaction. Subsequent attack by the thiol anion nucleophileat the 3-carbon of the 4,5-addition monoadduct would give the desireddiadduct. Khandelwal (1990) Food Chemistry 37:159 suggested that, in thepresence of a strong base, the 2,5-addition monoadduct may be convertedto the 4,5-addition monoadduct by the abstraction of the α-proton andconsequent protonation at the γ-carbon atom in the 2,5-additionmonoadduct. However, the attempt to convert the isolated 2,5-additionmonoadduct 3 to the 4,5-addition monoadduct in the presence of DBN wasunsuccessful as determined by means of ¹H NMR analysis. Moreover, the2,3-addition monoadduct 4 from the reaction between OSM andN-acetylcysteamine (route 3) that was isolated was believed to beunreactive to nucleophiles; thus, the formation of diadduct from 4 isnot likely. The differences in the aforementioned results and theexperimental observation of the time course ¹H NMR spectral study may beaccounted for by differences in the experimental conditions.

The formation of the 4,5-addition monoadduct was not detected by ¹H NMRanalysis in this reaction; Khandelwal et al. have reported similarresults for reactions of other thiols with ethyl and methyl sorbates.The 4,5-addition monoadduct is believed to be the more stable reactionproduct as it contains a C═C bond that is conjugated to the carbonylgroup. No evidence was obtained for the formation of this more stablemonoadduct. One explanation is that the 4,5-addition monoadduct may havebeen formed during the course of the reaction, but it was immediatelyattacked by the second equiv of the thiol anion to form the desireddiadduct.

The foregoing results demonstrate that both the selected thiol ester OSMand the ordinary ester OS react with N-acetylcysteamine, in the presenceof a base, to form their corresponding 2,5-monoadducts, and in additionOSM formed a 2,3-addition monoadduct. These reactions demonstrate thecapability of these prospective emollients to be attached to thesulfhydryl group of the protein residues of the skin, thus givinglong-lasting emolliency effects.

EXAMPLE 2 Synthesis of OCM

Crotonyl chloride was obtained from Aldrich Chemical, and octadecyl3-mercaptopropionate (hereinafter “OMP”) was obtained from EvansChemetics (Lexington, Mass.); both were used without furtherpurification. Pyridine was distilled from BaO and stored over 3 Åmolecular sieves. Tetrahydrofuran (hereinafter “THF”) was freshlydistilled from sodium/benzophenone. All glassware was dried with a flamebefore use.

To a 1-liter flask containing 13.5 g (0.129 mol) crotonyl chloridedissolved in approx. 250 mL THF was added dropwise a solution of 35.2 g(0.098 moles) OMP and 7.7 g (0.097 moles) pyridine in approx. 75 mL THF.Addition to the stirred solution was carried out over a period of 10minutes. A white solid formed immediately and continued to form. After 1hour of stirring at room temperature, the mixture was filtered. Thefiltrate was rotavapped by use of a 40° C. bath to yield 35.6 g (88%yield) of a slurry that solidified to a waxy white solid upon chilling.This material was purified by silica gel chromatography. A dry column(3.5 cm×60 cm) of 60 Å silica, 230-400 mesh (Baxter) was poured.Approximately 2.5 g of the solid reaction product was dissolved in asmall volume of chloroform. A small amount of silica was added, and themixture was rotavapped. The silica with the OCM adsorbed was placed atthe head of the column. Elution with 3% (v/v) hexanes in methylenechloride was carried out to yield 1.0 g of pure OCM as a crisp, whitesolid (R_(f)=0.47 in the same solvent). ¹H NMR (CDCl₃) δ 0.90 ppm [t,3H, —(CH₂)₁₇CH ₃], 1.2-1.3 [s, 30H, CH₃(CH ₂)₁₅—], 1.6 [m, 2H, —OCH₂CH₂—], 1.9 [dd, 3H, CH ₃CH═CH—], 2.6 [t, 2H, —CH ₂C(O)—], 3.18 [t, 2H,—SCH₂—], 4.10 [t, 2H —CO₂CH ₂—], 6.09 [m, 1H, CH₃CH═CH—], 6.9 [m, 1H,CH₃CH═CH—].

The reaction of OCM with N-acetylcysteamine was carried out at roomtemperature as follows: 22.0 mg of OCM was dissolved in 0.6 mL of CDCl₃and 5.7 μL of N-acetylcysteamine (1 equivalent) was added. The NMRspectrum was recorded and showed that no reaction had occurred. Then acatalytic amount (0.1 equiv) of the base DBN was added, and the NMRspectrum was recorded immediately and again after 5 minutes. By 5minutes, more than 60% of the OCM had reacted as judged by thediminished integration of the resonances at 6.9 ppm and 6.1 ppm due tothe vinyl protons of the crotonyl moiety of OCM. After 27 minutes, NMRshowed that complete reaction has occurred. A COSY spectrum confirmedthat the expected product, shown earlier herein, had been formed.Nucleophilic attack by the sulfur atom of N-acetylcysteamine, presumablyas the thiolate anion, at the β-position of the unsaturated thiol estergenerated the expected covalent adduct. NMR characteristics of theproduct are as follows: ¹H NMR (CDCl₃) δ 0.85 ppm [t, 3H, CH ₃(CH₂)₁₇—],1.2-1.3 [m, 30H, —(CH ₂)₁₅—], 1.24 [dd, 3H, CH ₃CH(S—)CH₂—], 1.6 [m, 2H,—CO₂CH₂CH ₂—], 2.0 [s, 3H, cysteamine CH ₃], 2.6 [m, 2H, —C(O)SCH₂CH₂—], 2.65 [m, 2H, cysteamine SCH ₂CH₂—], 2.7 [m, 2H, CH₃CH(S—)CH ₂—],3.2 [t, 2H, —C(O)SCH ₂CH₂—], 3.3 [q, 1H, CH₃CH(S—)CH₂—], 3.45 [m, 2H,cysteamine —SCH₂CH ₂NH—], 4.1 [t, 3H, —CO₂CH₂(CH₂)₁₆CH₃], 6.2 [br s, 1H,cysteamine NH].

EXAMPLE 3 Synthesis of DCPEG

DCPEG was synthesized according to the following scheme.

Poly(ethylene glycol) (hereinafter “PEG”) with an average molecularweight (M_(n)) of about 400 was obtained from Aldrich and was dried byheating at 70° C. under vacuum for three hours. Triethylamine, methylenechloride and pyridine were purified by distillation. THF was distilledfrom Na/benzophenone.

Preparation of PEG dimesylate was carried out as follows. PEG (3.65 g,18 mmol OH-ends) and 3.95 g triethylamine were dissolved in methylenechloride, chilled to 0° C. and then a five-fold excess ofmethanesulfonyl chloride dissolved in methylene chloride was addeddropwise. The solution was stirred at 0° C. for three hours and then itwas rotavapped to a syrup, taken up in water and the unreactedmethanesulfonyl chloride was destroyed by addition of NaHCO₃. Theproduct was then extracted into chloroform, dried with MgSO₄ androtavapped to yield 9.96 g of a light yellow oil (95% yield). ¹H NMR(CDCl₃) δ 3.07 ppm [s, 6H, CH ₃SO₂—], 3.6 [m, 28H, —OCH ₂CH ₂O—], 3.8[m, 4H, —SO₃CH₂CH ₂—], 4.4 [m, 4H, —SO₃CH ₂CH₂—].

To prepare the PEG dithiol, 5.0 g of the PEG dimesylate was added to anaqueous solution containing 53.8 mg diethylenetriaminepentaacetic acidand 2.85 g (2 equivalents) of thiourea. The pH was adjusted to 6.7, andthe reaction was refluxed for 2.5 hours. The reaction was then cooledand the isothiouronium salt was hydrolyzed by addition of 2.35 g ofNaHCO₃ (1.5 equivalents) followed by 1.5 hours of reflux. The solutionwas neutralized with 1 M H₂SO₄ and the PEG dithiol was extracted intochloroform, dried with MgSO₄ and rotavapped to yield 2.18 g of a lightamber oil.

Coupling of the PEG dithiol with crotonyl chloride to give DCPEG wascarried out as follows. A solution of 2.1 g PEG dithiol (9.0 mmolSH-ends) and 0.656 g (8.3 mmol) pyridine in 10 mL THF was placed in anaddition funnel and added dropwise to a stirred solution of 0.857 g (8.5mmol) crotonyl chloride in 20 mL THF. The solution instantly becamecloudy. After 16 hours the reaction was rotavapped to dryness and theresidue was taken up in chloroform, washed extensively with aqueousNaHCO₃ and dried to give 1.7 g of an amber oil (70% yield). ¹H NMR(CDCl₃) δ 1.88 ppm, [dd, J=7.6, 1.7 Hz, 6H, 2CH ₃—], 2.88 [t, J=6.6 Hz,4H, CH ₂—], 3.15 [t, J=6.6 Hz, 4H, —CH ₂—], 3.6-3.75 [m, —OCH ₂CH ₂O—],6.14 [m, 2H, 2 CH₃CH═CH—], 6.91 [m, 2H, 2 CH₃CH═CH—].

The reaction of DCPEG with N-acetylcysteamine was followed by NMR: 35.6mg of DCPEG was dissolved in 0.7 mL CDCl₃ and the spectrum was recordedbefore and after addition of N-acetylcysteamine (1 equivalent percrotonyl moiety). Then 0.1 equivalent of DBN was added. The reaction wasfound to be complete after 5 minutes, as evidenced by the disappearanceof the resonances at 6.14 and 6.91 ppm which correspond to the protonson the crotonyl double bond. NMR of the covalent N-acetylcysteamineadduct confirmed that addition to the β-position of the α,β-unsaturatedthiol ester had occurred.

The synthesis of DSPEG can be carried out by a procedure analogous tothat described for DCPEG above, except that sorboyl chloride is used inplace of crotonyl chloride.

CPEG and SPEG can be synthesized by a procedure analogous to thatdescribed for DCPEG above, except the amount of methanesulfonyl chlorideis reduced from a 5-fold excess to approximately one half equivalent(per OH-ends) to yield a mixture of unmodified PEG, PEG monomesylate andPEG dimesylate. The purified PEG monomesylate can then be treated withdiethylenetriaminepentaacetic acid and thiourea, followed by NaHCO₃, toyield PEG monothiol. PEG monothiol can be coupled to crotonyl chlorideto yield CPEG, or to sorboyl chloride to yield SPEG.

EXAMPLE 4 Preparation of Compositions

A suitable cream containing OCM for application to the skin wasformulated as follows. Percent by Ingredient weight (wt. %) A: Water67.7 Aculyn 33 2.5 B: Mineral Oil 20.0 Lanolin 4.0 Petrolatum 4.0Ethomeen C-25 0.7 C: Triethanolamine 1.1Mixing procedure:

First, 86 mg of OCM and 287 mg of part B were gently warmed for a fewseconds until OCM dissolved. Second, the solution was placed in a 60-70°C. bath for approximately 5 seconds. Then, 702 mg of part A also at60-70° C. was added to the solution. After addition of 11 mg of part C,the sample was quickly vortex-mixed and chilled to yield a cream. The pHwas found to be 8.2, in the range desired for deprotonation of cysteinesulfhydryl groups, tyrosine's —OH group, and protein —NH₃ ⁺ groups.

EXAMPLE 5 Preparation of Composition

A suitable cream for application to the skin is formulated as follows:Percent by Ingredient weight (wt. %) A: Water 67.7 Aculyn 33 2.5 B:Mineral Oil 20.0 Lanolin 4.0 Petrolatum 4.0 Ethomeen C-25 0.7 C:Triethanolamine 1.1Mixing procedure:

A suitable quantity of CPEG, DCPEG, SPEG, DSPEG, OSM, OCM, CMC or SMC orsome combination thereof is added to part B and the mixture is broughtto 60-70° C. After addition of part A, also at 60-70° C., part C isadded and the sample is mixed and quickly chilled to yield a cream. Theamount of part C is adjusted to produce a pH of approximately 8.2, inthe range desired for deprotonation of cysteine sulfhydryl groups,tyrosine hydroxyl groups, and —NH₃ ⁺ groups of lysine and the N-terminusof proteins.

All of the references cited herein are incorporated herein in theirentirety.

1-4. (canceled)
 5. A skin care composition comprising: a cosmeticallyacceptable carrier; and a skin care compound comprising at least onebonding agent and at least one characteristic use agent, wherein saidbonding agent is selected from the group consisting of crotonyl thiolesters, sorbyl thiol esters, and mixtures thereof, and wherein saidcharacteristic use agent is a chemical moiety selected from the groupconsisting of emollients and skin soothing agents, moisturizers,sunscreens, insecticides, antibacterials, fungicides, skin lighteningagents, artificial tanning agents, free-radical scavengers, antivirals,anti-acne agents, artificial tanning agents, anti wrinkle and anti-skinatrophy agents, antioxidants, and mixtures thereof.
 6. A skin carecomposition according to claim 5 wherein said bonding agent is selectedfrom the group consisting of crotonyl thiol esters, sorbyl thiol esters,and mixtures thereof; and wherein said characteristic use agent isselected from the group consisting of emollients and skin soothingagents, moisturizers, sunscreens, insecticides, antibacterials,fungicides, skin lightening agents, artificial tanning agents,free-radical scavengers, antivirals, anti-acne agents, artificialtanning agents, anti wrinkle and anti-skin atrophy agents, antioxidants,and mixtures thereof.
 7. A skin care composition according to claim 5wherein said skin care compound is characterized by the formula

wherein y is 1 or 2; and X is the characteristic use agent.
 8. A skincare composition according to claim 5 wherein said skin care compound ischaracterized by the formula

wherein each y is independently 1 or 2; and X is the characteristic useagent.
 9. A skin care composition according to claim 5 furthercomprising a catalytic amount of base.
 10. A skin care compositionaccording to claim 9, wherein said base is selected from the groupconsisting of aliphatic, heterocyclic and aromatic amines, imines, saltsof organic and inorganic acids, and mixtures thereof.
 11. A skin carecomposition according to claim 10 wherein said base is selected from thegroup consisting of 1,5-diazabicyclo[4.3.0]non-5-ene, bicarbonate,carbonate, triethanolamine, phosphate, and mixtures thereof.
 12. Amethod of conferring a skin care benefit by applying to mammalian skin askin care compound comprising at least one bonding agent and at leastone characteristic use agent, wherein said bonding agent is selectedfrom the group consisting of crotonyl thiol esters, sorbyl thiol esters,and mixtures thereof, and wherein said characteristic use agent isselected from the group consisting of emollients and skin soothingagents, moisturizers, sunscreens, insecticides, antibacterials,fungicides, skin soothing agents, skin lightening agents, artificialtanning agents, free-radical scavengers, antivirals, anti-acne agents,artificial tanning agents, anti wrinkle and anti-skin atrophy agents,antioxidants, and mixtures thereof.
 13. A method according to claim 12wherein said skin care compound is selected from the group consisting of

and mixtures thereof, wherein each y is independently 1 or 2; and X isthe characteristic use agent.